SUMMERY Degeneration of intervertebral disc (IVD) is closely associated with low back pain which afflicts 52 million individuals in the United States [21]. Since IVD is the largest avascular tissue in the human body, vital nutrients (e.g., oxygen and glucose) are delivered by diffusion and convection over a long distance through dense extracellular matrix to IVD cells. Therefore, poor nutrient supply has been suggested as a potential mechanism for disc degeneration [3,5,35]. The long term goals of our research are: (1) to understand mechanobiology of intervertebral disc and the mechanisms of disc degeneration and (2) to develop strategies to avoid or retard disc degeneration. Cells consume oxygen and glucose to produce energy that is an essential component in cellular matrix synthesis [61] for maintaining the integrity of tissue and preventing tissue degeneration. Adenosine triphosphate (ATP) is the major energy form which is mainly generated through glycolysis in the IVD [4]. During body motion, IVDs transmit large loads between bony vertebral bodies. Our recent theoretical study demonstrated that dynamic compression promoted glycolysis within the IVD by enhancing the transport of oxygen and lactate [42,43], suggesting that energy production of IVD cells can be promoted extrinsically by dynamic loading. Furthermore, previous studies showed that mechanical loading altered membrane transport of glucose and production of nitric oxide [8,16,17,62] which may affect cellular energy production intrinsically. The major objectives of this proposal are to examine (1) the overall effects of dynamic and static compression on ATP production of the IVD cells in the whole disc culture and (2) the intrinsic effect of mechanical loading on ATP production of the IVD cells. The hypotheses are proposed as the followings: (1) Cellular ATP production and transport of lactate and oxygen are promoted in the IVD under dynamic loading whereas static compression exhibits the reverse effect;and (2) Dynamic and static compression influence ATP production of IVD cells intrinsically. To test these hypotheses, we will (1) determine the concentrations of ATP, oxygen, and lactate in the IVD under static and dynamic compression (Specific Aim 1) and (2) determine the intrinsic effects of dynamic and static compression on the ATP production of IVD cells (Specific Aim 2). To achieve these specific aims, we will construct an organ culture system to provide an in-vitro culture environment and mechanical stimuli for IVD. Biochemical assays will be performed to assess concentrations of lactate and ATP in the IVD while oxygen concentration will be determined by an optic sensing system. The outcomes of the proposed studies will improve our understanding of cellular energy metabolism and nutrient transport in the IVD under mechanical loading and facilitate the development of new strategies to prevent disc degeneration. PUBLIC HEALTH RELEVANCE: Degeneration of intervertebral disc (IVD) is closely associated with low back pain which afflicts 52 million individuals in the United States. Poor nutrient supply has been suggested as a potential mechanism for disc degeneration. The outcomes of the proposed studies will improve our understanding of cellular energy metabolism and nutrient transport in the IVD under mechanical loading and facilitate the development of new strategies to prevent disc degeneration.